This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. Idiopathic (primary) pulmonary artery hypertension in children or adults (IPAH) is a progressive and fatal disease characterized by sustained elevations of pulmonary artery pressure of unknown etiology. Vasodilators are the mainstay of therapy, however 20-30% of children do not respond to vasodilators and non- responders have a poor prognosis. As the pathobiology is unknown, vasodilator therapy has significant morbidity and cost (~$50,000/year) and markers of vasodilator therapeutic efficacy are lacking, our long-term goal is to identify serum, diagnostic and prognostic markers of IPAH in children to improve long term outcomes. To pursue this goal, we have optimized an in-depth proteomics approach using abundant protein depletion coupled with intact protein separation methodologies and mass spectrometry to identify even low abundant serum proteins in children with pulmonary hypertension. In our preliminary data using longitudinal serum samples of children with IPAH we have already identified significant changes in a number of serum proteins in response to vasodilator therapy in children with IPAH. Every year Johns Hopkins Institutions directly generate about $10 billion in economic activity in the State of Maryland, a 43% increase from the $7 billion generated in 2002 and the equivalent of one of every twenty-four dollars in the state's economy today. In 2008, Johns Hopkins Institutions provided 45,000 jobs and created 700 new jobs each year since 2002. Directly and indirectly Johns Hopkins Institutions support more than 100,000 jobs in Maryland, one of every 29 in the state. In Baltimore City alone Johns Hopkins directly and indirectly supports 60,000 jobs, or 16.7 % of all City employment. This application will create or retain 2.4 jobs. PUBLIC HEALTH RELEVANCE: Idiopathic (primary) pulmonary artery hypertension in children or adults (IPAH) is a progressive and fatal disease characterized by sustained elevations of pulmonary artery pressure of unknown etiology. Vasodilators are the mainstay of therapy, however 20-30% of children do not respond to vasodilators and non-responders have a 30% five year survival. As the pathobiology is unknown, vasodilator therapy has significant morbidity and cost (~$50,000/year) and markers of vasodilator therapeutic efficacy are lacking, our long-term goal is to identify serum, diagnostic and prognostic markers of IPAH in children to improve long term outcomes.